W6 - GPCR's +

Question 1

What are the 4 major drug targets

Answer 1

Enzymes
Transporters
Ion channels
Receptors

Question 2

What is a receptor

Answer 2

Receptors are target molecules through which soluble physiological mediators can produce their desired biological effects

Question 3

What are the 4 different types of receptor

Answer 3

G protein coupled receptor (Metabotropic receptor)

Ligand gated ion channel

Enzyme coupled receptors

Nuclear receptors

Question 4

What is a metabotropic receptor

Answer 4

A type of membrane receptor that initiates a number of metabolic steps to modulate cell activity.

Question 5

What is a G Protein Coupled Receptor

Answer 5

A G protein coupled receptor is a transmembrane receptor that has seven domains which couple to g proteins to initiate signal transductions.

Question 6

What is the GPCR activated by

Answer 6

Photons
Hormones
Peptides
Peptidases

Question 7

Why are G protein coupled receptors important

Answer 7

• They are the largest family of cell surface receptors (approx 800genes)

Represent more than 50% of the current drug targets in a variety of fields ranging from stomach ulcers to migraines.

Question 8

What are the 6 Classes GPCR

Answer 8

Class A - Rhodopsin like
Class B - Secretin like
Class C - Metabotropic Glutamate pheromone 
Class D - Fungal pheromone
Class E - cAMP receptors
Class F - Frizzled/Smoothoned

Question 9

Describe the structure of a typical class a gpcr

Answer 9

There are 7 transmembrane domains which have a short N terminus and a c terminal tail. The domains are connected by intra and extra cellular loops.

Question 10

What do agonists bind to on a Class A gpcr

Answer 10

agonists bind to the extracellular loops and transmembrane domains

Question 11

Describe the structure of a typical class b gpcr

Answer 11

there are 7 transmembrane domains connected by intra and extra cellular loops.

Unlike class A it has a larger globular N terminus. In addition to this it has the familiar C terminal tail

Question 12

What is the role of the larger globular N terminus in class b gpcr’s

Answer 12

plays a role in agonist binding

Question 13

Describe the structure of a Class C gpcr

Answer 13

again it is made up of 7 transmembrane domains which are connected via intra and extra cellular loops. As well as having the C terminal Tail

What separates this is the large N terminal domain

Question 14

What is the role of the large N domain

Answer 14

binds agonists and form obligatory dimers

Question 15

What is a Dimer

Answer 15

is an oligomer consisting of two monomers joined by bonds that can be either strong or weak, covalent or intermolecular.

Question 16

What is the same in Class A Class B and Class C gpcr’s

Answer 16

7 Transmembrane domains

Connected via intra and extracellular loops

C terminal tail.

Question 17

Process by which GPCR’s are activated

Answer 17

Agonist binds to the receptor

receptor undergoes conformational change

increases affinity for heterotrimeric g protein

Question 18

What is the result of a GPCR being activated

Answer 18

There is an exchange of GDP to GTP from the G protein

The Subunits then dissociate and signal to different effectors.

Question 19

What does heterotrimeric g protein mean

Answer 19

Large 3 subunit g protein

Alpha subunit
Beta subunit
Gamma subunit

Question 20

What are the three major signaling events

Answer 20

Gas
Gai/o
Gaq/11

Question 21

describe the process of the Gas event occurring

Answer 21

The Gas subunit has a positive effect on adenylate cyclase which converts atp to cAMP. This means more cAMP is being produced which then interacts with protein kinase A.

Question 22

describe the process of the Gai/o event from occuring

Answer 22

Gai/o has an inhibitory effect on the adenylate cyclase catalytic domain. This means less cAMP is produced meaning that there is less interaction at the Protein kinase A structure

Question 23

describe the process of the Gaq/11 subunit

Hint
Cleave
Inner Membrane
Outer Membrane

Answer 23

Gaq/11 activates phospholipase which cleaves pip2 (fatty acid) into DAG and IP3.

DAG which remains in the membrane, acts as a tethering agent for PKC which moves to the membrane and becomes active.

IP3 binds to receptors on the endoplasmic reticulum as it moves to the cytosol, this increase the level of intracellular calcium

Question 24

What is desensitization

Answer 24

molecular mechanism that prevents continuous activation of GPCR’s.

Achieved by phosphorylation and or internalization

Critical to prevent uncontrolled signalling

Question 25

What is homologous desensitization

Answer 25

Effects are restricted to agonist acting through a specific receptor

Question 26

What is heterologous desensitization

Answer 26

effects can affect receptors that share a component of the same signaling code

Question 27

What is down regulation

Answer 27

reduction in number of functional receptors (permanent so new must be synthesized)

Question 28

How is GPCR desensitized

Answer 28

B arrestins bind to the receptor which recruit clathrin

which is involved in the internalization which puts the receptor in a endosome.

This is so that it can be either recycled or degraded in a lysosome

Question 29

What is tolerance

Answer 29

tolerance is the progressive reduction in the effectiveness of a drug, usually occurring over days or hours which is distinct from desensitization and down regulation